Insulin therapy is the most widely used clinical treatment for diabetes. Despite improvements in insulin therapy over the past few decades, the goal of reinstating complete physiological glucose homeostasis in diabetes patients have not been achieved. In particular, postprandial hyperglycemia remains an obstacle even with aggressive insulin therapy; in part because diabetes is a multihormonal disease, which involves the disturbed secretion of several hormones that physiologically, work in synergy to achieve normal glycemic control. See Kruger et al., Drugs (2004) 64 pp. 1419-1432.
Human islet amyloid polypeptide (hIAPP or amylin) is a neuroendocrine hormone produced in the pancreatic β-cells, which is stored in the insulin secretory granule and co-secreted with insulin. See Cooper, G. J. et al., Proc. Natl. Acad. Sci. (1987) Vol. 84 pp. 8628-8632; and Clark, A. et al., Lancet (1987) Vol. 2, pp. 231-234. In non-diabetic subjects, hIAPP complements the effects of insulin in postprandial glycemic control by suppressing glucagon secretion, and by helping regulate the rate of gastric emptying, and by inducing satiety to suppress food intake. See Scherbaum, W. A. Exp. Clin. Endocr. Diab. (1998) Vol. 106, pp. 97-102; and Rushing, P. A. et al., Endocrinology (2001) Vol. 142, pp. 5035-5038. hIAPP forms amyloid in the pancreatic islets of Langerhans in diabetes by an unknown mechanism. Pancreatic hIAPP amyloid deposits, are associated with reduced β-cell mass and contribute to type 2 diabetes and islet transplant failure. See Westermark, P., and Wilander, E. Diabetologia (1978) Vol. 15, pp. 417-421; Westermark, P. et al. Am. J. Pathol. (1987) Vol. 127, pp. 414-417; Westermark. P., Andersson. A., and Westermark. G. T. Physiol Rev (2011) Vol. 91, pp. 795-826; Cao P., Abedini A., Raleigh D. P. Curr. Opin. Struct. Biol. (2013) Vol. 23, pp. 82-88; and Potter, K. J., et al. Proc. Natl Acad. Sci. (2010) Vol. 107, pp. 4305-4310.
While hIAPP is deficient in both type 1 and type 2 diabetes patients (see Koda, J. E. et al., Lancet (1992) Vol. 339, pp. 1179-1180), clinical use of hIAPP is impractical because of its aggressive tendency to aggregate, which causes difficulties in formulation and storage and importantly, aggregates formed during hIAPP amyloid formation are toxic. A more soluble analog of hIAPP, pramlintide, i.e., Symlin™ (PM), has been developed and approved by the FDA, in which amino acid residues 25, 28, and 29 of endogenous hIAPP were substituted with proline. The substitution of the three prolines renders the hIAPP polypeptide non-amyloidgenic. However, pramlintide is not soluble at physiological pH. See Kruger et al., Drugs (2004) Vol. 64, pp. 1419-1432. Therefore, co-formulation of insulin, or an analog thereof, with pramlintide is not possible because hIAPP and pramlindtide are soluble at acidic pH (i.e., pH of about 4.0), whereas certain insulin agents, i.e., Humalog®, Apidra®, NovoLog®, Humulin®, Novolin®, Levemir® are formulated at near neutral pH (i.e., pH 7.0-7.8). This phenomenon requires separate injections of the pramlintide and insulin, leading to increased cost and reduced patient compliance.